The coincidence of chromosome 15 aberrations and β2-microglobulin gene mutations is causative for the total loss of human leukocyte antigen class I expression in melanoma

Annette Paschen, Norbert Arens, Antje Sucker, Karin M. Greulich-Bode, Ester Fonsatti, Annunziata Gloghini, Sandra Striegel, Nicole Schwinn, Antonino Carbone, Ralf Hildenbrand, Adelheid Cerwenka, Michele Maio, Dirk Schadendorf

Research output: Contribution to journalArticle

Abstract

Purpose: Total loss of surface presentation of human leukocyte antigen (HLA) class I molecules, protecting tumor cells from the recognition by cytotoxic host CD8+ T cells, is known to be caused by mutations in the β2-microglobulin (β2m) gene. We asked whether abnormalities of chromosome 15, harboring the β2m gene on 15q21, in addition to β2m gene mutations, are causative for the HLA class I-negative phenotype of melanoma cells. Experimental Design: To answer this, we established primary cell lines from the β2m-negative metastatic melanoma tissues of four different patients and analyzed them for β2m gene mutations and chromosome 15 aberrations, the latter by loss of heterozygosity analysis, fluorescence in situ hybridization (FISH), and multicolor FISH. Results: Mutations at the β2m gene level were detected in all cell lines. The loss of heterozygosity analysis of microsatellite markers located on chromosome 15 in three of the four cell lines pointed to an extensive loss of chromosome 15 material. Subsequent molecular cytogenetic analysis revealed the coexistence of apparently normal and rearranged versions of chromosome 15 in three cell lines whereas the fourth cell line solely showed rearranged versions. Two of the four cell lines exhibited a special type of intrachromosomal rearrangement characterized by FISH signals specific for the subtelomeric region of 15q at both ends of the chromosome and one centromeric signal in between. Conclusions: Our data indicate that the complete loss of HLA class I expression in melanoma cells is due to the coincidence of the following mutational events: (a) chromosome 15 instability associated with an extensive loss of genetic material and (b) β2m gene mutations.

Original languageEnglish
Pages (from-to)3297-3305
Number of pages9
JournalClinical Cancer Research
Volume12
Issue number11 I
DOIs
Publication statusPublished - Jun 1 2006

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Chromosomes, Human, Pair 15
Chromosomes, Human, Pair 2
HLA Antigens
Chromosome Aberrations
Melanoma
Mutation
Cell Line
Genes
Fluorescence In Situ Hybridization
Loss of Heterozygosity
Chromosomal Instability
Cytogenetic Analysis
Microsatellite Repeats
Research Design
Chromosomes
T-Lymphocytes
Phenotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The coincidence of chromosome 15 aberrations and β2-microglobulin gene mutations is causative for the total loss of human leukocyte antigen class I expression in melanoma. / Paschen, Annette; Arens, Norbert; Sucker, Antje; Greulich-Bode, Karin M.; Fonsatti, Ester; Gloghini, Annunziata; Striegel, Sandra; Schwinn, Nicole; Carbone, Antonino; Hildenbrand, Ralf; Cerwenka, Adelheid; Maio, Michele; Schadendorf, Dirk.

In: Clinical Cancer Research, Vol. 12, No. 11 I, 01.06.2006, p. 3297-3305.

Research output: Contribution to journalArticle

Paschen, A, Arens, N, Sucker, A, Greulich-Bode, KM, Fonsatti, E, Gloghini, A, Striegel, S, Schwinn, N, Carbone, A, Hildenbrand, R, Cerwenka, A, Maio, M & Schadendorf, D 2006, 'The coincidence of chromosome 15 aberrations and β2-microglobulin gene mutations is causative for the total loss of human leukocyte antigen class I expression in melanoma', Clinical Cancer Research, vol. 12, no. 11 I, pp. 3297-3305. https://doi.org/10.1158/1078-0432.CCR-05-2174
Paschen, Annette ; Arens, Norbert ; Sucker, Antje ; Greulich-Bode, Karin M. ; Fonsatti, Ester ; Gloghini, Annunziata ; Striegel, Sandra ; Schwinn, Nicole ; Carbone, Antonino ; Hildenbrand, Ralf ; Cerwenka, Adelheid ; Maio, Michele ; Schadendorf, Dirk. / The coincidence of chromosome 15 aberrations and β2-microglobulin gene mutations is causative for the total loss of human leukocyte antigen class I expression in melanoma. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 11 I. pp. 3297-3305.
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abstract = "Purpose: Total loss of surface presentation of human leukocyte antigen (HLA) class I molecules, protecting tumor cells from the recognition by cytotoxic host CD8+ T cells, is known to be caused by mutations in the β2-microglobulin (β2m) gene. We asked whether abnormalities of chromosome 15, harboring the β2m gene on 15q21, in addition to β2m gene mutations, are causative for the HLA class I-negative phenotype of melanoma cells. Experimental Design: To answer this, we established primary cell lines from the β2m-negative metastatic melanoma tissues of four different patients and analyzed them for β2m gene mutations and chromosome 15 aberrations, the latter by loss of heterozygosity analysis, fluorescence in situ hybridization (FISH), and multicolor FISH. Results: Mutations at the β2m gene level were detected in all cell lines. The loss of heterozygosity analysis of microsatellite markers located on chromosome 15 in three of the four cell lines pointed to an extensive loss of chromosome 15 material. Subsequent molecular cytogenetic analysis revealed the coexistence of apparently normal and rearranged versions of chromosome 15 in three cell lines whereas the fourth cell line solely showed rearranged versions. Two of the four cell lines exhibited a special type of intrachromosomal rearrangement characterized by FISH signals specific for the subtelomeric region of 15q at both ends of the chromosome and one centromeric signal in between. Conclusions: Our data indicate that the complete loss of HLA class I expression in melanoma cells is due to the coincidence of the following mutational events: (a) chromosome 15 instability associated with an extensive loss of genetic material and (b) β2m gene mutations.",
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T1 - The coincidence of chromosome 15 aberrations and β2-microglobulin gene mutations is causative for the total loss of human leukocyte antigen class I expression in melanoma

AU - Paschen, Annette

AU - Arens, Norbert

AU - Sucker, Antje

AU - Greulich-Bode, Karin M.

AU - Fonsatti, Ester

AU - Gloghini, Annunziata

AU - Striegel, Sandra

AU - Schwinn, Nicole

AU - Carbone, Antonino

AU - Hildenbrand, Ralf

AU - Cerwenka, Adelheid

AU - Maio, Michele

AU - Schadendorf, Dirk

PY - 2006/6/1

Y1 - 2006/6/1

N2 - Purpose: Total loss of surface presentation of human leukocyte antigen (HLA) class I molecules, protecting tumor cells from the recognition by cytotoxic host CD8+ T cells, is known to be caused by mutations in the β2-microglobulin (β2m) gene. We asked whether abnormalities of chromosome 15, harboring the β2m gene on 15q21, in addition to β2m gene mutations, are causative for the HLA class I-negative phenotype of melanoma cells. Experimental Design: To answer this, we established primary cell lines from the β2m-negative metastatic melanoma tissues of four different patients and analyzed them for β2m gene mutations and chromosome 15 aberrations, the latter by loss of heterozygosity analysis, fluorescence in situ hybridization (FISH), and multicolor FISH. Results: Mutations at the β2m gene level were detected in all cell lines. The loss of heterozygosity analysis of microsatellite markers located on chromosome 15 in three of the four cell lines pointed to an extensive loss of chromosome 15 material. Subsequent molecular cytogenetic analysis revealed the coexistence of apparently normal and rearranged versions of chromosome 15 in three cell lines whereas the fourth cell line solely showed rearranged versions. Two of the four cell lines exhibited a special type of intrachromosomal rearrangement characterized by FISH signals specific for the subtelomeric region of 15q at both ends of the chromosome and one centromeric signal in between. Conclusions: Our data indicate that the complete loss of HLA class I expression in melanoma cells is due to the coincidence of the following mutational events: (a) chromosome 15 instability associated with an extensive loss of genetic material and (b) β2m gene mutations.

AB - Purpose: Total loss of surface presentation of human leukocyte antigen (HLA) class I molecules, protecting tumor cells from the recognition by cytotoxic host CD8+ T cells, is known to be caused by mutations in the β2-microglobulin (β2m) gene. We asked whether abnormalities of chromosome 15, harboring the β2m gene on 15q21, in addition to β2m gene mutations, are causative for the HLA class I-negative phenotype of melanoma cells. Experimental Design: To answer this, we established primary cell lines from the β2m-negative metastatic melanoma tissues of four different patients and analyzed them for β2m gene mutations and chromosome 15 aberrations, the latter by loss of heterozygosity analysis, fluorescence in situ hybridization (FISH), and multicolor FISH. Results: Mutations at the β2m gene level were detected in all cell lines. The loss of heterozygosity analysis of microsatellite markers located on chromosome 15 in three of the four cell lines pointed to an extensive loss of chromosome 15 material. Subsequent molecular cytogenetic analysis revealed the coexistence of apparently normal and rearranged versions of chromosome 15 in three cell lines whereas the fourth cell line solely showed rearranged versions. Two of the four cell lines exhibited a special type of intrachromosomal rearrangement characterized by FISH signals specific for the subtelomeric region of 15q at both ends of the chromosome and one centromeric signal in between. Conclusions: Our data indicate that the complete loss of HLA class I expression in melanoma cells is due to the coincidence of the following mutational events: (a) chromosome 15 instability associated with an extensive loss of genetic material and (b) β2m gene mutations.

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